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  • C04B35/00—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
  • C04B35/622—Forming processes; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
  • C04B35/626—Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B
  • C04B35/63—Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B using additives specially adapted for forming the products, e.g.. binder binders
  • C04B35/632—Organic additives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
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• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
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  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
  • C07D209/16—Tryptamines
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
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  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems

Definitions

• the present invention relates to new sulphonamide derivatives, with the general formula (I), as well as to their physiologically acceptable salts, the processes for their preparation, their application as medicaments in human and/or veterinary therapy and the pharmaceutical compositions that contain them.
• the new compounds object of the present invention can be used in the pharmaceutical industry as intermediates and for preparing medicaments.
• the superfamily of serotonin receptors includes 7 classes (5-HT 1 -5-HT 7 ) encompassing 14 human subclasses [D. Hoyer, et al., Neuropharmacology, 1997 , 36 , 419].
• the 5-HT 6 receptor is the latest serotonin receptor identified by molecular cloning both in rats [F.J. Monsma, et al., Mol. Pharmacol., 1993 , 43 , 320; M. Ruat, et al., Biochem. Biophys. Res. Commun., 1993, 193 , 268] and in humans [R. Kohen, et al., J. Neurochem., 1996, 66 , 47].
• Compounds with 5-HT 6 receptor antagonistic activity are useful for the treatment of various disorders of the Central Nervous System and of the gastrointestinal tract, such as irritable bowel syndrome.
• Compounds with 5-HT 6 receptor antagonistic activity are useful in the treatment of anxiety, depression and cognitive memory disorders [M. Yoshioka, et al., Ann. NY Acad. Sci., 1998, 861 , 244; A. Bourson, et al., Br. J. Pharmacol. , 1998, 125 , 1562; D.C. Rogers, et al., Br. J. Pharmacol. Suppl., 1999, 127 , 22P; A. Bourson, et al., J. Pharmacol. Exp.
• Compounds with 5-HT 6 receptor antagonistic activity are useful for treating infantile hyperkinesia (ADHD, attention deficit / hyperactivity disorder) [W.D. Hirst, et al., Br. J. Pharmacol. , 2000 , 130 , 1597; C. protagonist, et al., Brain Research, 1997 , 746 , 207; M.R. Pranzatelli, Drugs of Today, 1997 , 33 , 379].
• ADHD attention deficit / hyperactivity disorder
• Patent application WO 01/32646 describes sulphonamides derived from bicycles, with 6 members each, aromatic or heteroaromatic with 5-HT 6 receptor antagonistic activity.
• Patent application EP 0733628 describes sulphonamides derived from indole with an 5-HT 1F receptor antagonistic activity useful for treating migraines.
• the study of the scientific literature and patents indicates that small structural variations give rise to agonist or antagonist compounds of various receptors of serotonin that are useful for treating different diseases, depending on the receptor for which they show affinity.
• EP-A-0 733 628 and WO-A-9 846 570 disclose structurally related 5-HT antagonists.
• FR-A-1 601 070 and EP-A-0 747 353 disclose structurally related compounds.
• the present invention provides new compounds with serotonin 5-HT6 receptor antagonistic activity useful in the preparation of a medicament for prevention or treatment of various disorders of the Central Nervous System, and in particular anxiety, depression, cognitive memory disorders and senile dementia or other dementia processes in which there is a predominant cognition deficit, psychosis, infantile hyperkinesia (ADHD, attention deficit / hyperactivity disorder) and other disorders mediated by the serotonin 5-HT 6 receptor in mammals, including man.
• ADHD attention deficit / hyperactivity disorder
• the compounds object of the present invention have the general formula (I) wherein A represents a substituent selected from among:
• the alkyl term C 1 -C 4 represents a linear or branched hydrocarbon chain including 1 to 4 atoms of carbon, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec -butyl and tert-but yl .
• the present invention also relates to the physiologically acceptable salts of the compounds with the general formula (I), particularly the addition salts of mineral acids such as hydrochloric, hydrobromic, phosphoric, sulphuric, nitric acids, and of organic acids such as citric, maleic, fumaric, tartaric acids or their derivatives, p- toluensulphonic acid, methansulphonic acid, camphorsulphonic acid, etc.
• mineral acids such as hydrochloric, hydrobromic, phosphoric, sulphuric, nitric acids
• organic acids such as citric, maleic, fumaric, tartaric acids or their derivatives, p- toluensulphonic acid, methansulphonic acid, camphorsulphonic acid, etc.
• the reaction between the compounds with the general formula (II) and (III) is carried out in the presence of an organic solvent such as an alkyl ether, particularly diethyl ether, or a cycloalkyl ether, particularly tetrahydrofurane or dioxane, a halogenated organic hydrocarbon, particularly methylene chloride or chloroform, an alcohol, particularly methanol or ethanol, an aprotic dipolar solvent, particularly acetonitrile, pyridine or dimethylformamide, or any other suitable solvent.
• an organic solvent such as an alkyl ether, particularly diethyl ether, or a cycloalkyl ether, particularly tetrahydrofurane or dioxane, a halogenated organic hydrocarbon, particularly methylene chloride or chloroform, an alcohol, particularly methanol or ethanol, an aprotic dipolar solvent, particularly acetonitrile, pyridine or dimethylformamide, or any other suitable solvent.
• the reaction preferably is carried out in the presence of a suitable inorganic base such as hydroxides and carbonates of alkali metals, or in the presence of an organic base, particularly triethylamine or pyridine.
• a suitable inorganic base such as hydroxides and carbonates of alkali metals
• an organic base particularly triethylamine or pyridine.
• reaction temperatures range from 0 ° C to room temperature, and the reaction time is between 5 minutes and 24 hours.
• the resulting sulphonamide can be isolated by evaporating the solvent, adding water and eventually adjusting the pH so that it is obtained as a solid that can be isolated by filtration; or it can be extracted by a solvent immiscible with water such as chloroform and purified by chromatography or recrystallisation from a suitable solvent.
• the compounds with the general formula (II) are commercially available or can be prepared according to standard methods or by methods analogous to those described in the literature [E.E. Gilbert, Synthesis, 1969 , 1 , 3] and the compounds with the general formula (III) can be prepared according to standard methods or by methods analogous to those described in the literature [J.E. Macor, R. Post and K. Ryan, Synt Comm., 1993 , 23 , 1, 65-72.; J. Nicolas, C. Dumont, J. Laurent and N. Nédélec, Eur. J. Med. Chem., 1987 , 22 , 33-43; M.L. Saccarello, R. Stradi, Synthesis, 1979 , 727].
• the compounds with the general formula (I), wherein R 1 , R 2 , R 4 , n and A have the meanings indicated above and R 3 represents a C 1 -C 4 alkyl, can be prepared by alkylation of a compound with the general formula (I), wherein R 1 , R 2 , R 4 , n and A have the meanings indicated above and R 3 represents an atom of hydrogen, with an alkyl halide or a dialkyl sulphate.
• the reaction preferably is carried out in the presence of a suitable base such as hydroxides and carbonates of alkali metals, metal hydrides, alkoxides such as sodium methoxide or potassium tert-butoxide, organometallic compounds such as butyl lithium or tert-butyl lithium, in the presence of an organic solvent such as an alkyl ether, particularly diethyl ether, or a cycloalkyl ether, particularly tetrahydrofurane or dioxane, a hydrocarbon, particularly toluene, an alcohol, particularly methanol or ethanol, an aprotic dipolar solvent, particularly acetonitrile, pyridine or dimethylformamide, or any other suitable solvent.
• a suitable base such as hydroxides and carbonates of alkali metals, metal hydrides, alkoxides such as sodium methoxide or potassium tert-butoxide, organometallic compounds such as butyl lithium or tert-butyl lithium
• the reaction can take place in both an acid and a basic medium, in a suitable solvent at temperatures between 25 and 150° C.
• Suitable basic conditions include inorganic bases such as sodium or potassium hydroxide, or organic bases such as pyrrolidine or triethylamine in solvents such as methanol or ethanol.
• solvents such as methanol or ethanol.
• solutions of sodium methoxide in methanol at reflux range from 1 to 48 hours.
• Suitable acidic conditions include hydrochloric acid in ethanol or trifluoroacetic acid in acetic acid at temperatures between 50 and 100° C and reaction times ranging from 1 to 48 hours.
• the resulting sulphonamide can be isolated by dilution in water, eventually adjusting the pH, to obtain it as a solid that can be isolated by filtration; or it can be extracted with a solvent immiscible with water such as chloroform and purified by chromatography or by recrystallisation from a suitable solvent.
• Hydrogenation takes place with the aid of a metallic catalyst such as palladium, platinum or rhodium on a support such as carbon, aluminum oxide or barium sulphate, preferably palladium over carbon, with an initial hydrogen pressure of between 1 and 10 atmospheres, preferably between 2 and 5 atmospheres, in a solvent such as methanol or ethanol.
• a metallic catalyst such as palladium, platinum or rhodium on a support such as carbon, aluminum oxide or barium sulphate, preferably palladium over carbon
• the reaction time ranges from 1 hour to 3 days.
• the resulting sulphonamide can be isolated by filtering the catalyst and concentrating the filtrate at reduced pressure.
• the product recovered can be used as such or it can be purified by chromatography or by recrystallisation from a suitable solvent.
• the pharmacologically acceptable salts of compounds with the general formula (I) can be conventionally prepared by reaction with a mineral acid, such as hydrochloric, hydrobromic, phosphoric, sulphuric, nitric acids or with organic acids such as citric, maleic, fumaric, tartaric acids or their derivatives, p-toluensulphonic acid, methansulphonic acid, etc., in a suitable solvent such as methanol, ethanol, ethyl ether, ethyl acetate, acetonitrile or acetone and obtained with the usual techniques of precipitation or crystallisation of the corresponding salts.
• a mineral acid such as hydrochloric, hydrobromic, phosphoric, sulphuric, nitric acids or with organic acids such as citric, maleic, fumaric, tartaric acids or their derivatives, p-toluensulphonic acid, methansulphonic acid, etc.
• a suitable solvent such as methanol
• any of the synthesis sequences described, or in the preparation of the sintones used it may be necessary and/or desirable to protect sensitive or reactive groups in some of the molecules employed. This can be performed by means of conventional protective groups such as those described in the literature [Protective groups in Organic Chemistry, ed J. F.W. McOmie, Plenum Press, 1973 ; T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Chemistry, John Wiley & sons, 1991 ].
• the protective groups can be removed in a suitable latter stage by known methods.
• the invention provides pharmaceutical compositions that comprise, in addition to an acceptable pharmaceutical excipient, at least one compound with the general formula (I) or one of its physiologically acceptable salts.
• the invention also relates to the use of a compound with the general formula (I) and its physiologically acceptable salts in the preparation of a medicament having serotonin 5HT 6 receptor antagonistic activity, useful for preventing or treating various disorders of the Central Nervous System, and particularly anxiety, depression, cognitive memory disorders and senile dementia processes, and other dementias in which predominates a cognition deficit, psychosis, infantile hyperkinesia (ADHD, attention deficit /hyperactivity disorder) and other disorders mediated by the serotonin 5-HT 6 receptor in mammals, including man.
• ADHD attention deficit /hyperactivity disorder
• Example 7 Preparation of N-[3-(2-dimethylaminoethyl)-1 H -indol-5-yl]-5-chloro-3-methyl-benzo[b]thiophene-2-sulphonamide.
• Example 26 Preparation of N-[3-(2-diethylaminoethyl)-1 H -indol-5-yl]-N-ethyl-naphthalene-2-sulphonamide.
• Example 18 Preparation of N-[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1 H -indol-5-yl]naphthalene-1-sulphonamide.
• Example 12 Preparation of N-[3-(1-methyl-piperidin-4-yl)-1 H -indol-5-yl]naphthalene-1-sulphonamide.
• Example 3 Preparation of N-[3-(2-diethylaminoethyl)-1 H -indol-5-yl]naphthalene-1-sulphonamide hydrochloride.
• N-[3-(2-diethylaminoethyl)-1 H -indol-5-yl]naphthalene-1-sulphonamide (example 2) are dissolved in 10 ml of ethanol, and 0.6 ml of a 4.2 N solution of hydrochloric acid in ethanol are added. It is allowed to crystallise at room temperature.
• the commercial membrane is diluted (1:40 dilution) with the binding buffer: 50 mM Tris-HCl, 10 mM MgCl 2 , 0.5 mM EDTA (pH 7.4).
• the radioligand used is [ 3 H]-LSD at a concentration of 2.7 nM with a final volume of 200 ⁇ l. incubation is initiated by adding 100 ⁇ l of membrane suspension, ( ⁇ 22.9 ⁇ g membrane protein), and is prolonged for 60 minutes at a temperature of 37° C.
• the incubation is ended by fast filtration in a Brandel Cell Harvester through fiber glass filters made by Schleicher & Schuell GF 3362 pretreated with a solution of polyethylenimine at 0.5 %.
• the filters are washed three times with three milliliters of buffer Tris-HCI 50 mM pH 7.4.
• the filters are transferred to flasks and 5 ml of Ecoscint H liquid scintillation cocktail are added to each flask.
• the flasks are allowed to reach equilibrium for several hours before counting with a Wallac Winspectral 1414 scintillation counter.
• Non-specific binding is determined in the presence of 100 ⁇ M of serotonin. Tests were made in triplicate.
• the daily posology in human medicine are between 1 milligram and 500 milligrams of product, which can be given in one or more administrations.
• the compositions are prepared in forms compatible with the route of administration used, such as tablets, sugar-coated pills, capsules, suppositories, solutions or suspensions. These compositions are prepared by known methods and comprise between 1 and 60% by weight of the active ingredient (compound with the general formula I) and 40 to 99% by weight of a suitable pharmaceutical excipient compatible with the active ingredient and the physical form of the composition used.
• the formula of a tablet containing a product of the invention is shown.
• Example of formula per tablet Example 1 5 mg Lactose 60 mg Crystalline cellulose 25 mg K 90 Povidone 5 mg Pregelatinised starch 3 mg Colloidal silicon dioxide 1 mg Magnesium stearate 1 mg Total weight per tablet 100 mg

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